Aging is a complex biological process that is modulated by numerous genetic and environmental factors. Among the environmental factors, dietary nutrients are critical in modulating healthspan and lifespan. Nutrient imbalance has been shown to post great risks to human health, especially to the elderly population. Dietary macronutrients, such as sugar, protein and fat, can interact with each other and have significant impact on health. Therefore, it is critical to take into account diet composition in elucidating molecular mechanisms of aging and in developing effective interventions for promoting healthy aging. Mitochondrial genes have been shown to play a key role in modulating lifespan and are implicated in numerous age-related diseases, such as Parkinsons and Alzheimers diseases. However, how mitochondrial genes interact with dietary macronutrients to modulate lifespan and healthspan remains incompletely elucidated. To this end, we have focused on studying the function of ATP synthase subunit d (ATPsyn-d) in modulating lifespan under various dietary conditions in Drosophila. Last year, we have published a paper in Cell Reports reporting that ATPsyn-d interacts with dietary macronutrients to modulate lifespan at least partially through TOR signaling pathway. We have further demonstrated that Rapamycin, a drug known to promote longevity in various species including flies and rodents, significantly reduces lifespan of flies with reduced expression of ATPsyn-d. These findings stress the importance to take into account the genetic background in implementing interventions for promoting longevity and healthspan and provide a framework for designing effect aging interventions. In this reporting cycle, we have extended this line of work on ATPsyn-d in modulating lifespan and investigated which tissue is critical for the effect of ATPsyn-d on lifespan. We have shown that ATPsyn-d knockdown in adult fat tissue is sufficient to extend lifespan in Drosophila. Similar to ubiquitous ATPsyn-d knockdown, this lifespan extension depends on the composition of the diet, particularly the carbohydrate-to-protein ratio. A manuscript is in preparation to describe these tissue-specific findings. In summary, we have made significant progress towards understanding molecular mechanisms underlying aging and age-related diseases. We have extended our studies on the function of ATP synthase in modulating lifespan besides its well-known function in generating ATP. We have investigated the gene-environment interactions in aging, which is a key to tackle aging and age-related diseases. These studies are valuable for advancing the objectives of the Translational Gerontology Branch and the mission of the NIA to understand the basic biology of aging and develop efficient interventions for humans.